CN104693240A - Method for preparing minodronic acid - Google Patents
Method for preparing minodronic acid Download PDFInfo
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- CN104693240A CN104693240A CN201510092154.2A CN201510092154A CN104693240A CN 104693240 A CN104693240 A CN 104693240A CN 201510092154 A CN201510092154 A CN 201510092154A CN 104693240 A CN104693240 A CN 104693240A
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Abstract
The invention relates to preparation of minodronic acid. The minodronic acid is used for treating osteoporosis, and achieves an effect of preventing and treating osteoporosis by inhibiting synthetase activity of farnesyl pyrophosphate (FPP) in osteoclasts, inhibiting bone absorption of osteoclasts and reducing bone turnover. The method comprises the steps of condensing and cyclizing ethyl trans-4-oxo-2-butenoate which serves as an initial raw material with 2-aminopyridine to generate 2-[imidazo[1,2-alpha]pyridin-3-yl]ethyl acetate, hydrolyzing with acid to obtain 2-[imidazol(1,2-alpha)pyridin-3-yl] acetic acid, and reacting with phosphorus tribromide and phosphorous acid to generate minodronic acid.
Description
Technical field
The invention belongs to organic chemical synthesis technical field, relate to the preparation method of minodronic acid.
Background technology
Minodronic acid (Minodronic acid) structural formula is as follows, its chemistry 1-hydroxyl-2-[imidazo (1,2-a) pyridin-3-yl] ethylidene by name) two banks-hydrate, CAS:127657-42-5.This product is crystallization or the crystalline powder of white-micro-red and white.This grade is insoluble in water, is substantially insoluble to ethanol.This product dissolves in sodium hydroxide testing liquid.Chemical formula is C
9h
12n
2o
7p
2, relative molecular weight is 321.16.Minodronic acid (Minodronic acid) is the nitrogenous fragrant heterocyclic ring di-phosphonic acid salt of the third generation, this product is by Japanese ONO Pharmaceutical Co., Ltd. and Japanese Astellas Pharmaceutical Co., Ltd joint development, in July, 2006 to Japanese health ministry submit applications, get permission traded commodity name first on January 21st, 2009 and be respectively Recalbon (little wild medicine) and Bonoteo (Astellas pharmacy).
This product is used for the treatment of osteoporosis, by suppressing farnesyl pyrophosphate (FPP) synthase activity in osteoclast, suppresses the bone resorption of osteoclast, reduces bone conversion, plays the osteoporotic effect of control.The tablet of 1 mg, 1 day 1 time, 1 time 1.The comparative advantages of this medicine show: compare with diphosphonate conventional clinically at present, it suppresses the activity of bone resorption strong, it is 2 times of incadronate disodium, 10 times of the sodium of clinic effect of alendronate, 100 times of Pamidronate Disodium, and side effect of digestive tract incidence is few compared with existing bisphosphonate class of drugs.This product cost is low, and profit is high.
Summary of the invention
The technical problem to be solved in the present invention is to provide the preparation method of minodronic acid.
The object of this invention is to provide a kind of preparation method of minodronic acid.The method comprises the following steps: with trans 4-oxygen base-2-butylene acetoacetic ester for starting raw material, 2-［ imidazo (1 is generated with PA cyclic condensation, 2-α) pyridin-3-yl ］ ethyl acetate, 2-［ imidazo (1 is obtained by acid hydrolysis, 2-α) pyridin-3-yl ］ acetic acid, then react with phosphorus tribromide, phosphorous acid and generate minodronic acid.
The synthetic route of minodronic acid of the present invention:
Embodiment
Further illustrate the present invention by the following examples, but not as limitation of the present invention.
embodiment:
The synthesis of mono-Walk: C
In 5 L there-necked flasks, add 104.0 g A, then add 2 L ethanol, start to be stirred to entirely molten, system is faint yellow clear liquor.Take 88.0 g sodium bicarbonates and add reaction system, system presents muddy shape.Slowly be warming up to 70 DEG C.Constant pressure funnel at the uniform velocity instills 134.0 g B, controls temperature of reaction 70-80 DEG C, and stirring reaction 3h, TLC detect raw material point and disappear, and naturally cool to suction filtration after room temperature, filtrate is in 45 DEG C of concentrating under reduced pressure.Concentrate to obtain oily matter 1.6 L acetic acid ethyl dissolutions, 3 times are washed with water (1.6 L x 3), use 50 g anhydrous sodium sulfate drying 2 hours again, suction filtration, filtrate, in 45 DEG C of concentrating under reduced pressure removing ethyl acetate, obtains 183.1 g dark reddish-brown oil thing C, yield 85.8%, without the need to purifying, be directly used in next step reaction.
The preparation of second step: D
By 181 g C, 305 mL tetrahydrofuran (THF) solution transfer to 3 L there-necked flasks, then add 453 mL concentrated hydrochloric acids and 906 mL water, start to stir, open and be heated to back flow reaction 2h, be slightly chilled to 60 DEG C, add 50 g gacs, reflux decolour 1.5h.Slightly be chilled to 60 DEG C, suction filtration, filtrate 60 DEG C of concentrating under reduced pressure obtain oily matter, and pale yellow crystals solid, appears in cooling, add mixed solution (acetone: methyl alcohol=4:1) 0.57 L of acetone and methyl alcohol, at 35-40 DEG C, stir 0.5h, at this temperature suction filtration, solid is in 45 DEG C of vacuum-dryings to constant weight, obtain off-white color crystalline solid 91.9 g D, yield 58.9%.
The preparation of the 3rd step: E
In 10 L reaction flasks, add 2.3 L chlorobenzenes, nitrogen protection, under stirring, add 90.0 g D and 125.0 g phosphorous acid, open and be heated to 110 DEG C, at the uniform velocity drip 194 mL phosphorus tribromides, drip and finish, maintain 110-120 DEG C of reaction 6h.TLC detection reaction terminates, naturally cool to room temperature, incline and upper liquid, add concentrated hydrochloric acid 1280 mL and water 2560 mL, be heated to (95-100 DEG C) 3h that refluxes, stop heating, be slightly chilled to 80 DEG C, suction filtration while hot, obtain faint yellow clear liquor, filtrate, in 60 DEG C of concentrated by rotary evaporations to about 250 mL, is cooled to room temperature, the mixed solvent of acetone 1500 mL and methyl alcohol 1250 mL is added under ice bath, ice bath stirs 2h, suction filtration, and filter cake 45 DEG C of vacuum-dryings are to constant weight, obtain 68.0 g off-white powder shape solid E, yield 39.1%.
Claims (7)
1. a preparation method for minodronic acid, is characterized in that comprising the following steps:
Mono-Walk: with A and B for starting raw material is under organic solvent and alkaline condition, control temperature of reaction 60-70 DEG C, cyclic condensation prepares Compound C;
Bis-Walk: with C be starting raw material by acid hydrolysis, control temperature of reaction 95-100 DEG C, obtain intermediate D;
3rd step: with D be raw material in organic solvent with phosphorous acid, phosphorus tribromide reaction after prepare Compound D through acidic hydrolysis again
。
2. preparation method according to claim 1, the alkaline reagents that the first step is reacted used is sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, and organic solvent is acetonitrile, methyl alcohol, ethanol.
3. preparation method according to claim 1, the alkaline reagents that the first step is reacted used is sodium bicarbonate; Organic solvent is ethanol.
4. preparation method according to claim 1, second step and three-step reaction acid reagent used are hydrochloric acid.
5. preparation method according to claim 1, three-step reaction organic solvent used is toluene, chlorobenzene, controls temperature of reaction 80-120 DEG C.
6. preparation method according to claim 1, three-step reaction organic solvent used is chlorobenzene; Control temperature of reaction 110 DEG C.
7. preparation method according to claim 1, three-step reaction D: phosphorous acid: the mol ratio of phosphorus tribromide is 1:3:4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510092154.2A CN104693240A (en) | 2015-03-02 | 2015-03-02 | Method for preparing minodronic acid |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510092154.2A CN104693240A (en) | 2015-03-02 | 2015-03-02 | Method for preparing minodronic acid |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175446A (en) * | 2015-10-17 | 2015-12-23 | 青岛辰达生物科技有限公司 | Preparation method of minodronic acid for treating osteoporosis |
| CN105467027A (en) * | 2015-11-18 | 2016-04-06 | 北京万全德众医药生物技术有限公司 | A method of separating and measuring compounds related to a minodronic acid intermediate through gas chromatography |
| CN107033187A (en) * | 2017-04-28 | 2017-08-11 | 江苏笃诚医药科技股份有限公司 | A kind of preparation method of minodronic acid |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101531681A (en) * | 2008-03-10 | 2009-09-16 | 北京德众万全医药科技有限公司 | High-purity minodronic acid and preparation method thereof |
| US20090312551A1 (en) * | 2005-06-13 | 2009-12-17 | Satish Chandra Pandey | Process for producing biphosphonic acids and forms thereof |
| CN102344463A (en) * | 2011-10-17 | 2012-02-08 | 南京艾德凯腾生物医药有限责任公司 | Method for preparing 1-hydroxy-2-(imidazo [1, 2-a] pyridine-3-radical) ethylidene-1, 1-bisphosphonic acid compound |
-
2015
- 2015-03-02 CN CN201510092154.2A patent/CN104693240A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090312551A1 (en) * | 2005-06-13 | 2009-12-17 | Satish Chandra Pandey | Process for producing biphosphonic acids and forms thereof |
| CN101531681A (en) * | 2008-03-10 | 2009-09-16 | 北京德众万全医药科技有限公司 | High-purity minodronic acid and preparation method thereof |
| CN102344463A (en) * | 2011-10-17 | 2012-02-08 | 南京艾德凯腾生物医药有限责任公司 | Method for preparing 1-hydroxy-2-(imidazo [1, 2-a] pyridine-3-radical) ethylidene-1, 1-bisphosphonic acid compound |
Non-Patent Citations (1)
| Title |
|---|
| 王伟 等: "米诺膦酸的合成", 《中国医药工业杂志》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175446A (en) * | 2015-10-17 | 2015-12-23 | 青岛辰达生物科技有限公司 | Preparation method of minodronic acid for treating osteoporosis |
| CN105175446B (en) * | 2015-10-17 | 2017-03-22 | 青岛辰达生物科技有限公司 | Preparation method of minodronic acid for treating osteoporosis |
| CN105467027A (en) * | 2015-11-18 | 2016-04-06 | 北京万全德众医药生物技术有限公司 | A method of separating and measuring compounds related to a minodronic acid intermediate through gas chromatography |
| CN105467027B (en) * | 2015-11-18 | 2021-09-21 | 北京万全德众医药生物技术有限公司 | Method for separating and measuring minodronate intermediate related substances by gas chromatography |
| CN107033187A (en) * | 2017-04-28 | 2017-08-11 | 江苏笃诚医药科技股份有限公司 | A kind of preparation method of minodronic acid |
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Application publication date: 20150610 |